LOS ANGELES (August 8, 2005; 5:00 p.m., EDT) -- By the time the humangenome was mapped, cancer researchers had already begun investigatingthe proteins that were encoded by these newly identified genes. As themolecular engines that control all functions of the body, scientistswanted to find out how proteins work to promote health, or malfunctionto cause disease. Subsequently, their discoveries have led to thedevelopment of a whole new arsenal of therapies designed to targetproteins in cancer cells. But not all patients respond to treatmentwith these targeted drugs, prompting researchers to look for molecularclues within tumor cells that cause resistance to treatment.
Now, cancer researchers at Cedars-Sinai Medical Center haveidentified a protein called EMP-1 that is present in the tumors ofpatients who fail to respond to treatment with gefitinib, or IressaTM,a drug that has limited success in the treatment of patients with nonsmall-cell lung cancer -- the most common and deadly form of lungcancer. The study, conducted in both laboratory tests and patients withadvanced non small-cell lung cancer who were treated with gefitinib, ispublished on-line during the week of August 8 -- 12, in an "EarlyEdition" of the Proceedings of the National Academy of Sciences, andmay ultimately help physicians identify patients who would benefit fromtreatment with gefitinib.
"Our results show that the EMP-1 protein is a biomarker forresistance to treatment with gefitinib and may enable us to identifypatients who won't respond to the drug," said David Agus, M.D., seniorauthor of the study and Research Director at the Louis WarschawProstate Cancer Center at the Samuel Oschin Comprehensive CancerInstitute at Cedars-Sinai Medical Center. "If we know who won'trespond, we can explore other treatment options sooner and usegefitinib, when patients will benefit. This means we will be able tomaximize use of this drug and treat more patients effectively."
Gefitinib is a drug approved by the Food and DrugAdministration to treat patients with NSCLC only after conventionaltreatment with chemotherapy has failed. It is taken in pill form andworks by blocking the action of a key growth-signaling pathway in aprotein called the epidermal growth factor receptor (EGFR). Butgefitinib shrinks tumors in only about 11 percent of patients with nonsmall-cell lung cancer, and most of these patients eventually developresistance to the drug.
Given the limitations of gefitinib, scientists began lookingfor proteins within non small-cell lung cancer tumor cells that mightindicate who would be most responsive to the drug. The first of theirefforts resulted in two important studies published early last yearthat identified specific mutations within the EGFR pathway linked topatient response to gefitinib. However, these mutations correlated onlywith a partial or complete response to gefitinib in NSCLC patients,while 30 percent or more of the patients receiving the treatmentreported stable disease.
"While these observations are very important, they still posevast imprecision in predicting which patients would benefit fromtreatment with gefitinib, and emphasize the need for understanding themechanisms responsible for gefitinib resistance," said Anjali Jain,Ph.D., the first author of the study and a research scientist atCedars-Sinai Medical Center.
To identify the proteins involved in resistance to gefitinib,the researchers first developed a resistant tumor model in thelaboratory. This was done by implanting a type of prostate cancer inmice that was "androgen-independent," or that was resistant totreatment with hormone blocking drugs and grew independently oftestosterone production. The researchers chose prostate cancer tumorsfor this study because, similar to non small-cell lung cancer, prostatecancer tumors become resistant to treatment, have the same EGFRprotein-signaling pathway and have been found to respond to treatmentwith gefitinib in early clinical trials and laboratory studies.
The mice were then treated with 100 mg/kg of gefitinib for fivedays per week. Every three weeks thereafter the tumors were removed andimplanted in other mice until a gefitinib resistant tumor had beengenerated. The investigators then compared the resistant tumors tothose tumors that were newly implanted and had not yet acquiredresistance to the drug (gefitinib-sensitive). They found that aparticular gene, EMP-1, was significantly expressed in thegefitinib-resistant tumors, whereas it was not expressed in thegefitinib-sensitive model.
"This tumor model was generated in such a way that it closelymimicked acquired resistance to gefitinib and EMP-1 was identified as asurface biomarker whose expression correlated with the development ofresistance to gefitinib," Agus said. "Molecular diagnostics, such asthis, are extremely important as we attempt to personalize cancertreatments in the next decade."
To confirm whether or not EMP-1 was present in patients with nonsmall-cell lung cancer who were being treated with gefitinib inclinical trials, the investigators examined tumor samples from 39patients. They found that none of the patients who responded totreatment with gefitinib expressed EMP-1. Alternatively, EMP-1 waspresent in 14 patients (28 percent) who had non small-cell lung cancerthat had either stabilized or progressed. Importantly, however, onepatient who initially did not express EMP-1 and had responded totreatment with gefitinib, later acquired resistance to the drug, andEMP-1 was significantly expressed when the cancer recurred.
"This tells us that the absence of EMP-1 does not completelypredict whether a person won't stop responding to gefitinib. However,it appears that testing for the presence of EMP-1 at the outset oftreatment may help physicians predict which patients won't benefit fromthe drug," Jain explained. "Importantly, we found that EMP-1 is notonly a marker for patients who won't respond to gefitinib, but also forthose who will later develop resistance to the drug."
To confirm that EMP-1 was also present in patients with typesof non small-cell lung cancer that do not respond to gefitinib, theinvestigators examined tumor samples from patients with adenocarcinomaand squamous cell carcinoma. They found that EMP-1 was expressed in 66percent of the squamous cell carcinomas and 40.9 percent of those withadenocarcinoma, confirming that the presence of EMP-1 is directlylinked to Iressa-resistance.
"This is an important new tool in the treatment of lung cancerwhich needs to be confirmed in ongoing large clinical trials," saidRonald Natale, M.D., an oncologist at the Cedars-Sinai OutpatientCancer Center at the Samuel Oschin Comprehensive Cancer Institute and aprincipal investigator on clinical trials with gefitinib, including theIressa Dose Evaluation in Advanced Lung Cancer Trial 2 (IDEAL 2) thatprovided the basis for the initial approval of Iressa by the FDA.
One of only five hospitals in California whose nurses have beenhonored with the prestigious Magnet designation, Cedars-Sinai MedicalCenter is one of the largest non-profit academic medical centers in theWestern United States. For 17 consecutive years, it has been named LosAngeles' most preferred hospital for all health needs in an independentsurvey of area residents. Cedars-Sinai is internationally renowned forits diagnostic and treatment capabilities and its broad spectrum ofprograms and services, as well as breakthroughs in biomedical researchand superlative medical education. It ranks among the top 10non-university hospitals in the nation for its research activities andwas recently fully accredited by the Association for the Accreditationof Human Research Protection Programs, Inc. (AAHRPP). Additionalinformation is available at www.csmc.edu.
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